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A proteomic approach for characterizing trastuzumab-emtansine modified for nuclear directed localization that enhances cytotoxicity identifies regulatory nuclear transport receptor.

ABSTRACT: We used the approved antibody-drug conjugate trastuzumab-emtansine and the HER2+ cell line SKBR3. We also used a novel technology termed cell accumulator (Accum) that enables mAbs to escape endosome entrapment and localize to the cell nucleus without abrogating antibody affinity or specificity to target antigens. Accum harbors a well-known nuclear localization signal (NLS) sequence recognized by the classic nuclear transportation receptor (NTR) complex alpha-importin/importin-beta. Accum-modification of T-DM1 resulted in a significant increase in cytotoxic potency. We sought to understand the mechanisms through which Accum-T-DM1 localized to the nucleus and increased tumor cell killing effectiveness.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Vincent Lacasse

LAB HEAD: Jeffrey Victor Leyton

PROVIDER: PXD014786 | Pride | 2021-09-08

REPOSITORIES: Pride

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Publications

A Novel Proteomic Method Reveals NLS Tagging of T-DM1 Contravenes Classical Nuclear Transport in a Model of HER2-Positive Breast Cancer.

Lacasse Vincent V Beaudoin Simon S Jean Steve S Leyton Jeffrey V JV

Molecular therapy. Methods & clinical development 20200901

The next breakthrough for protein therapeutics is effective intracellular delivery and accumulation within target cells. Nuclear localization signal (NLS)-tagged therapeutics have been hindered by the lack of efficient nuclear localization due to endosome entrapment. Although development of strategies for tagging therapeutics with technologies capable of increased membrane penetration has resulted in proportional increased potency, nonspecific membrane penetration limits target specificity and, ...[more]

PMID: 33024794

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Project description:Analysis of genes that were differentially expressed in mutant VUB03_DM1 as compared to controls VUB01 and SA01 Mesodermal Precursors Cells. Embryonic stem (ES) cell lines provide, theoretically, unlimited access to any needed amount of any specific cell phenotype of an organism, due to their unique capacities at indefinite self-renewal and pluripotency (Smith 2001; Trounson 2006). These properties allow using the progeny of ES cell lines to model human pathologies (Martinat, Shendelman et al. 2004; Lerou and Daley 2005; Ben-Nun and Benvenisty 2006). In particular, human ES cell lines derived from embryos characterized as gene-carriers following pre-implantation genetic diagnosis (PGD) for any one of major monogenic diseases (Pickering, Minger et al. 2005; Mateizel, De Temmerman et al. 2006) may be considered as perfect cellular replicas of those diseases, as they exhibit the exact genotypes associated to them. Here, we confirm this hypothesis by demonstrating that the cell progeny of an ES cell line derived from an embryo with myotonic dystrophy type 1 (DM1) displayed the morphological stigma associated to the expression of the mutant gene âso-called intranuclear foci- as well as abnormal alternate splicing of the insulin receptor, a characteristic feature of DM1. Further differential transcriptomic analysis of the DM1 gene-carrying cells with phenotypically similar populations from native ES cell lines revealed abnormal expression of 89 genes, among which 48 were down-regulated and 39 over-expressed. This study demonstrates that DM1, though a disease with relatively late clinical onset, is associated with expression of genetic defects early on during development. It underlines the value of PGD-derived ES cell lines as a tool to decipher molecular mechanisms of genetic diseases. Ben-Nun, I. F. and N. Benvenisty (2006). Human embryonic stem cells as a cellular model for human disorders. Mol Cell Endocrinol 252(1-2): 154-9. Lerou, P. H. and G. Q. Daley (2005). Therapeutic potential of embryonic stem cells. Blood Rev 19(6): 321-31. Martinat, C., S. Shendelman, et al. (2004). Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES- derived cell model of primary Parkinsonism. PLoS Biol 2(11): e327. Mateizel, I., N. De Temmerman, et al. (2006). Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum Reprod 21(2): 503-11. Pickering, S. J., S. L. Minger, et al. (2005). Generation of a human embryonic stem cell line encoding the cystic fibrosis mutation deltaF508, using preimplantation genetic diagnosis. Reprod Biomed Online 10(3): 390-7. Smith, A. G. (2001). Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol 17: 435-62. Trounson, A. (2006). The production and directed differentiation of human embryonic stem cells. Endocr Rev 27(2): 208-19. Keywords: disease state analysis Two controls hES-derived MPC (VUB01 and SA01) and one mutant hES-derived MPC (VUB03_DM1), with three biological replicats for each

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	18-07-31_ACCUM.raw	Raw
	18-07-31_HERCEPTIN.raw	Raw
	18-07-31_NT.raw	Raw
	18-07-31_TDM1.raw	Raw
	18-08-14_ACCUM.raw	Raw